DESCRIPTION (applicant's abstract): There is a high incidence of infectious disease in heroin-dependent individuals. In spite of the major health issues surrounding heroin use, very few studies have examined the impact of heroin on immune status. Specific Aim I provides the first direct comparisons of the impact of heroin, morphine, and their metabolites on immune status, as measured by alterations of inflammatory immune responses. The project assesses the effect of heroin, 6-monoacetylmorphine, the active metabolite of heroin, morphine and its major metabolites, morphine-3beta-glucuronide and morphine-6-beta-glucuronide, on several models of inflammation including: (1) the acute neutrophil-mediated inflammatory response to an intraperitoneal injection of thioglycolate; (2) the early inflammatory response to bacterial infection, using well-established non-infectious, infectious-non-disseminating, and infectious-disseminating bacteria; and (3) the assessment of contact hypersensitivity, a more complex inflammatory response that requires prior sensitization to antigen and involves memory T-lymphocytes. Specific Aim II tests the hypothesis that heroin and morphine induce pharmacologically-specific alterations of inflammatory responses that are mediated by distinct opioid receptors. The second specific aim identifies the subtype of opioid receptor that mediates the effect of heroin and morphine on inflammatory responses. Antagonism studies test the following opioid receptor-selective antagonists: N-methylnaltrexone, a nonselective opioid receptor antagonist that does not cross the blood brain barrier, beta-funaltrexamine (beta-FNA), an irreversible antagonist selective for the mu-opioid receptor, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a somatostatin-derived peptide antagonist for the mu-opioid receptor, nor-binaltorphimine (nor-BNI), an antagonist selective for the kappa opioid receptor, and naltrindole (NTI, a selective delta opioid receptor antagonist. Additionally, the use of 3-methoxynaltrexone, a putative heroin-selective antagonist, is used to distinguish opioid receptors for heroin-induced modulation of inflammatory responses. Specific Aim 3 tests the hypothesis that the self-administration of heroin induces alterations of inflammatory responses that are different from passive administration of drug. The self-administration paradigm provides a clinically relevant methodology for the assessment of heroin's effects on inflammation. The plan is to compare heroin-induced alterations of inflammation using self-administration to those following passive drug administration. Collectively, the proposed experiments promise to advance our understanding of the health consequences of heroin and morphine, providing important information to guide clinical care and advance development of new therapeutic approaches.